Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

Angew Chem Int Ed Engl. 2020 Aug 3;59(32):13295-13304. doi: 10.1002/anie.202002546. Epub 2020 May 26.


The F1 FO -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.

Keywords: ATP synthesis; F-ATP synthase; drug discovery; inhibitors; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proton-Translocating ATPases / antagonists & inhibitors*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Benzamides / toxicity
  • Diarylquinolines / pharmacology*
  • Drug Synergism
  • Embryonic Stem Cells / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidines / toxicity
  • Structure-Activity Relationship


  • Bacterial Proteins
  • Benzamides
  • Diarylquinolines
  • Enzyme Inhibitors
  • Pyrimidines
  • bedaquiline
  • Bacterial Proton-Translocating ATPases